1. Technical Field
The present invention relates generally to a process for the preparation of carboxamide compounds. More particularly, the present invention relates to a process for preparing 10-methoxycarbamazepine (10-methoxy-5H-dibenz(b,f)azepin-5-carboxamide), an intermediate used in the preparation of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (i.e., oxcarbazepine).
2. Description of the Related Art
The present invention relates to a process for the preparation of carboxamide compounds. One such carboxamide compound is oxcarbazepine (also known as 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide of Formula I:
Oxcarbazepine is an anticonvulsant drug used in the treatment of epilepsy and is commercially sold under the name Trileptal®. Oxcarbazepine is structurally related to carbamazepine (also known as 5H-dibenzo[b,f]azepine-5-carboxamide of Formula II above, of which oxcarbazepine is a keto derivative. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 1240, monograph 6998; and Physician's Desk Reference, “Trileptal,” 58th Edition, p. 2324-2328 (2003). Oxcarbazepine shares many chemical and pharmacological properties with carbamazepine. Both are highly lipophilic and neutral at most pH values and both are used mainly for the treatment of partial seizures and generalized tonic-clonic seizures. Oxcarbazepine, however, is often used for patients who are intolerant to carbamazepine treatment.
A number of processes to prepare oxcarbazepine are known. For example, U.S. Pat. No. 3,642,775 (“the '775 patent”) discloses the synthesis of oxcarbazepine by hydrolysis of 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide in a dilute mineral acid or in the mixture of water and a water-miscible solvent in the presence of an acid ion exchanger in its acidic form. The synthesis of the starting material 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide is disclosed in the '775 patent using phosgene gas, which is toxic and subject to strict regulations.
Another example of a process for the preparation of oxcarbazepine is disclosed in U.S. Pat. No. 5,808,058. In this process, 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide is obtained by carbamoylation of 10-methoxy-5H-dibenz[b,f]azepine with an isocyanic acid generated in situ by the reaction of alkali or alkaline earth cyanates and an acid selected from sulfuric acid, anhydrous hydrochloric acid, anhydrous hydrobromic acid, glacial acetic acid, formic acid, monochloroacetic acid, monobromoacetic acid, dichloroacetic acid, trichloroacetic acid, propionic acid, or 2-chloropropionic acid. The 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide product is then hydrolyzed with an acid to obtain oxcarbazepine. Alternatively, the hydrolysis can be performed first. However, when an alkali metal cyanate and an acid are added to 10-methoxyiminostilbene, the enol-ether moiety of 10-methoxyiminostilbene undergoes hydrolysis to give the corresponding oxo-iminodibenzyl which does not undergo a carboxamidation reaction with HOCN. Accordingly, the major disadvantage of this process includes competing reactions resulting in the formation of oxo-iminodibenzyl and other impurities, which makes the process less economical.
Yet another example of a process for the preparation of oxcarbazepine is disclosed in U.S. Pat. No. 6,670,472. In this process, 10-methoxy-5H-dibenz[b,f]azepine (10-methoxyiminostilbene) is reacted with a cyanic acid generated in situ by the reaction of an alkali metal cyanate and a mild aromatic acidic reagent such as benzoic acid. The 10-methoxycarbamazepine may then be hydrolyzed to form oxcarbazepine. The major disadvantage of this process includes competing reactions resulting in the formation of oxo-iminodibenzyl and other impurities (see, e.g., Scheme 5), which makes the process less economical.
Accordingly, there remains a need for an improved process for the production of carboxamide compounds such as oxcarbazepine and its intermediates which is economical, safe, and wherein the reaction provides a product in a relatively high yield and high purity.